Aetiology

Dry eye disease (DED) is a multifactorial ocular surface disease characterised by loss of tear film homeostasis due to tear film hyperosmolarity and instability, ocular surface inflammation and damage, and neurosensory abnormality.[1][2] This results in ocular discomfort, dryness, and visual disturbance.[3]

Dry eye occurs with aqueous deficiencies (due to Sjögren syndrome and non-Sjögren syndrome DED) or evaporative abnormalities (either intrinsic or extrinsic and due to increased tear film evaporation).[3][9][10] Patients often have a component of both types of dry eye. Therefore, each underlying component should be considered on a continuum and not as separate entities.[3]

Aqueous-deficient causes:

  • Sjögren syndrome

    • Primary: autoimmune inflammation and destruction of the lacrimal and salivary glands, which occurs without any other associated systemic disease

    • Secondary: can occur in rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), and mixed connective tissue disorder.

  • Non-Sjögren syndrome

    • Lacrimal gland deficiency (e.g., T-cell infiltration of lacrimal glands in HIV infection, sarcoidosis, age-related)

    • Lacrimal gland obstruction (e.g., trachoma)

    • Reflex block (e.g., diabetes mellitus, cranial nerve VII damage)

    • Medications (e.g., oral contraceptives, antihistamines, beta-blockers, anticholinergics, diuretics, some psychotropic drugs).

Evaporative causes:

  • Intrinsic

    • Meibomian oil deficiency: directly affects tear film evaporation

    • Lid disorders (e.g., blepharitis): eyelid margin inflammation and obstruction of the meibomian glands can lead to reduced lipid layers within tear films and increased tear film evaporation[3][Figure caption and citation for the preceding image starts]: BlepharitisPrivate collection of Dr Jonathan Smith and Dr Philip Severn; used with permission [Citation ends].com.bmj.content.model.Caption@2a378576

    • Low blink rate (e.g., Parkinson's disease): directly affects tear film evaporation[11]

    • Medications (e.g., retinoids).

  • Extrinsic

    • Vitamin A deficiency: occurs due to reductions in conjunctival goblet cell numbers and tear film instabilities (aqueous deficiency may also occur in some patients)[3]

    • Preservatives in topical ophthalmic medications (e.g., benzalkonium chloride): can cause corneal surface cell damage that interferes with surface wetting[3][12]

    • Contact lens use: occurs due to increased tear film thinning times which causes tear film hyperosmolarity[13]

    • Ocular surface disease (e.g., diabetes, allergic conjunctivitis).[3][14]

Environmental causes

  • Milieu interieur

    • Low blink rate

    • Ageing: older patients have naturally reduced lacrimal gland dysfunction secondary to ductal obstruction[3][6]

    • Low androgen pool: androgen deficiency associated with postmenopausal hormone replacement therapy may contribute to meibomian gland dysfunction and evaporative abnormality[3][15][16]

    • Medications

    • Wide lid aperture gaze position.

  • Milieu exterieur

    • Low relative humidity: increases tear film evaporation[3]

    • High wind velocity: increases tear film evaporation[3]

    • Occupational environments: occupations requiring sustained visual attention (e.g., computer use) can cause intrinsic evaporative abnormalities from low blink rates which directly affect tear film evaporation.[3]

Other causes include corneal and lens surgery (e.g., prior keratoplasty, cataract surgery, and keratorefractive surgery), eyelid surgery (e.g., punctal cautery, prior ptosis repair, blepharoplasty, entropion/ectropion repair), eyelid malposition (e.g., lagophthalmos, lid retraction, proptosis), thyroid eye disease, graft-versus-host disease, and Stevens-Johnson syndrome.[2]

Pathophysiology

The pathophysiology of DED is multifactorial. The most important factors are tear film hyperosmolarity, tear film instability, and ocular surface inflammation.

Tear film hyperosmolarity occurs due to aqueous deficiency or increased evaporative tear loss. The increase in the tear film osmolarity (which can occur as a primary event) leads to ocular surface inflammation, inducing the loss of corneal epithelial and goblet cells. Consequently, this amplifies tear film instability which can further increase tear film osmolarity, leading to a 'vicious cycle' that perpetuates the DED state.[3]​​

It has been recommended that the diagnosis of Sjögren syndrome should be made when criteria are met, without distinguishing it as primary or secondary. Studies have demonstrated that circulating antibodies and infiltration of the lacrimal gland by T and B lymphocytes, dendritic cells, macrophages, and other mononuclear cells are responsible for the tissue destruction in Sjögren syndrome, culminating in aqueous deficiency.[3]​​[17]

On the other hand, tear film instability, which can occur without prior tear film hyperosmolarity, plays a central role in the pathophysiology of evaporative DED.[3]​ This leads to tear film break-up in the inter-blink interval and tear hyperosmolarity, resulting in surface epithelial damage and disturbance of glycocalyx and goblet cell mucins. More subtle degrees of tear film instability may also predispose a patient to dry eye complications in response to ocular surface stress (e.g., laser refractive surgery).[3]​ Preservatives in ophthalmic drops can also cause epithelial cell damage, cell death by apoptosis, and a decrease in goblet cell density.[18]

Many other factors, depending on the underlying aetiology, can contribute to this cycle.​[3]​​

Classification

The 2017 Tear Film and Ocular Surface Society International Dry Eye Workshop II (TFOS DEWS II) classification of DED[3]​​

  • Aqueous deficiency: includes sub-groups of Sjögren syndrome and non-Sjögren syndrome DED

  • Evaporative: includes sub-groups of intrinsic causes (which directly affect evaporation of the tear film) and extrinsic causes (which cause ocular surface abnormality leading to increased evaporation).

Patients often have a component of both types of DED. The updated 2017 classification scheme introduces several new terminologies for subtyping of DED and DED-mimicking conditions, based on the different degrees of symptoms and signs.

  • DED: symptomatic involvement of dry eye with associated ocular surface signs

  • Other ocular surface disease differential diagnoses: refers to conditions that may mimic or masquerade as DED (e.g., lagophthalmos leading to DED). In these circumstances, treating the condition may result in improvement of DED symptoms and signs, but it is unlikely to achieve long-term success unless the underlying pathology is also addressed

  • Symptoms without signs:

    • neuropathic pain: lesion or disease within somatosensory system that results in ocular pain symptoms disproportionately outweighing the signs

    • pre-clinical dry eye state: symptoms consistent with DED but in the absence of signs, especially when the symptoms are intermittent.

  • Signs without symptoms:

    • reduced corneal sensitivity: exhibiting signs of ocular surface disease but without symptoms, due to reduced corneal sensation

    • predisposition to dry eye: exhibiting signs of ocular surface disease but without symptoms during a preoperative examination for cataract or other ocular surgeries. This may signify early disease that might increase the risk of symptomatic DED following the ocular surgery.

Use of this content is subject to our disclaimer